Objective: Parental psychopathology is a significant risk factor for mental health challenges in offspring, but the nature and magnitude of this link in Indigenous Peoples is not well understood. This systematic review examined the emotional and behavioral functioning of the offspring of Indigenous parents with mental health challenges. Method: We searched MEDLINE, EMBASE, PsycINFO, CINAHL, and Web of Science from their inceptions until April 2020. Studies were included if they included assessments of emotional, behavioral, or other psychological outcomes in the offspring of Indigenous parents with a mental health challenge. Results: The 14 studies eligible for review were focused on parental substance misuse ( n = 8), maternal internalizing (i.e., depression, anxiety) issues ( n = 5), and poor overall parental mental health ( n = 4). In 11 studies, parental substance misuse, depression, and/or overall mental health challenges were associated with 2 to 4 times the odds of offspring externalizing and internalizing behaviors as compared to offspring of Indigenous parents without mental health challenges. Conclusion: The findings suggest higher risks of mental health challenges among offspring of Indigenous parents with psychiatric difficulties than among Indigenous children of parents without similar difficulties. Knowledge of these phenomena would be improved by the use of larger, more representative samples, culturally appropriate measures, and the engagement of Indigenous communities. Future studies should be focused on both risk and resilience mechanisms so that cycles of transmission can be interrupted and resources aimed at detection, prevention, and treatment optimally allocated.